Peroxisome proliferator-activated receptor α(PPARα),a ligand-activated nuclear receptor critical for systemic lipid homeostasis,has been shown closely related to cardiac remodeling.However,the roles of cardiomyocyte PPARα in pressure overload-induced cardiac remodeling remains unclear because of lacking a cardiomyocyte-specific Ppara-deficient(Ppara△CM)mouse model.This study aimed to determine the specific role of cardiomyocyte PPARα in transverse aortic constriction(TAC)-induced cardiac remodeling using an inducible Ppara△cM mouse model.Ppara△CM and Pparafl/fl mice were randomly subjected to sham or TAC for 2 weeks.Cardiomyocyte PPARα deficiency accelerated TAC-induced cardiac hypertrophy and fibrosis.Transcriptome analysis showed that genes related to fatty acid metabolism were dramatically downregulated,but genes critical for glycolysis were markedly upregulated in Ppara△CM hearts.Moreover,the hypertrophy-related genes,including genes involved in extracellular matrix(ECM)remodeling,cell adhesion,and cell migration,were upregulated in hypertrophic Ppara△CM hearts.Western blot analyses demonstrated an increased HIF1a protein level in hypertrophic Ppara△CM hearts.PET/CT analyses showed an enhanced glucose uptake in hypertrophic Ppara△CM hearts.Bioenergetic analyses further revealed that both basal and maximal oxygen consumption rates and ATP production were significantly increased in hypertrophic Pparanm hearts;however,these increases were markedly blunted in Ppara△CM hearts.In contrast,hypertrophic Ppara△CM hearts exhibited enhanced extracellular acidification rate(ECAR)capacity,as reflected by increased basal ECAR and glycolysis but decreased glycolytic reserve.These results suggest that cardiomyocyte PPARα is crucial for the homeostasis of both energy metabolism and ECM during TAC-induced cardiac remodeling,thus providing new insights into potential therapeutics of cardiac remodeling-related diseases.

Xia Wang;Xin-xin Zhu;Shi-yu Jiao;Dan Qi;Bao-qi Yu;Guo-min Xie;Ye Liu;Yan-ting Song;Qing Xu;Qing-bo Xu;Frank J.Gonzalez;Jie Du;Xiao-min Wang;Ai-juan Qu

Department of Physiology and Pathophysiology,School of Basic Medical Sciences,Capital Medical University,Beijing 100069,China;Key Laboratory of Remodeling-Related Cardiovascular Diseases,Ministry of Education;Beijing Key Laboratory of Metabolic Disorder-Related Cardiovascular Diseases,Beijing 100029,China;Core Facility Centre,Capital Medical University,Beijing 100069,China;Department of Cardiology,The First Affiliated Hospital,School of Medicine,Zhejiang University,Hangzhou 310003,China;Laboratory of Metabolism,Center for Cancer Research,National Cancer Institute,National Institutes of Health,Bethesda,MD,USA;Beijing Anzhen Hospital,Capital Medical University,Beijing Collaborative Innovation Center for Cardiovascular Disorders,Beijing Institute of Heart,Lung & Blood Vessel Disease,Beijing 100029,China

中国药理学报（英文版）

[1]Xia Wang;Xin-xin Zhu;Shi-yu Jiao;Dan Qi;Bao-qi Yu;Guo-min Xie;Ye Liu;Yan-ting Song;Qing Xu;Qing-bo Xu;Frank J.Gonzalez;Jie Du;Xiao-min Wang;Ai-juan Qu-.Cardiomyocyte peroxisome proliferator-activated receptor α is essential for energy metabolism and extracellular matrix homeostasis during pressure overload-induced cardiac remodeling)[J].中国药理学报（英文版）,2022(05):1231-1242

Ppara,Pparafl,HIF1a,Bioenergetic,Pparanm

Cardiomyocyte,peroxisome,proliferator,activated,receptor,essential,energy,metabolism,extracellular,matrix,homeostasis,during,pressure,overload,induced,cardiac,remodeling,Peroxisome,PPAR,ligand,nuclear,critical,systemic,lipid,has,been,shown,closely,related,However,roles,cardiomyocyte,remains,unclear,because,lacking,specific,deficient,mouse,This,study,aimed,determine,transverse,aortic,constriction,TAC,using,inducible,cM,mice,were,randomly,subjected,sham,weeks,deficiency,accelerated,hypertrophy,fibrosis,Transcriptome,analysis,showed,that,genes,fatty,dramatically,downregulated,but,glycolysis,markedly,upregulated,hearts,Moreover,including,involved,ECM,adhesion,migration,hypertrophic,blot,analyses,demonstrated,increased,protein,level,PET,enhanced,glucose,uptake,further,revealed,both,basal,maximal,oxygen,consumption,rates,ATP,production,significantly,however,these,increases,blunted,In,contrast,exhibited,acidification,ECAR,capacity,reflected,by,decreased,glycolytic,reserve,These,results,suggest,crucial,thus,providing,new,insights,into,potential,therapeutics,diseases

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